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1.
Int J Mol Sci ; 25(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731821

RESUMO

In contrast to cats and dogs, here we report that the α2-adrenergic receptor antagonist yohimbine is emetic and corresponding agonists clonidine and dexmedetomidine behave as antiemetics in the least shrew model of vomiting. Yohimbine (0, 0.5, 0.75, 1, 1.5, 2, and 3 mg/kg, i.p.) caused vomiting in shrews in a bell-shaped and dose-dependent manner, with a maximum frequency (0.85 ± 0.22) at 1 mg/kg, which was accompanied by a key central contribution as indicated by increased expression of c-fos, serotonin and substance P release in the shrew brainstem emetic nuclei. Our comparative study in shrews demonstrates that clonidine (0, 0.1, 1, 5, and 10 mg/kg, i.p.) and dexmedetomidine (0, 0.01, 0.05, and 0.1 mg/kg, i.p.) not only suppress yohimbine (1 mg/kg, i.p.)-evoked vomiting in a dose-dependent manner, but also display broad-spectrum antiemetic effects against diverse well-known emetogens, including 2-Methyl-5-HT, GR73632, McN-A-343, quinpirole, FPL64176, SR141716A, thapsigargin, rolipram, and ZD7288. The antiemetic inhibitory ID50 values of dexmedetomidine against the evoked emetogens are much lower than those of clonidine. At its antiemetic doses, clonidine decreased shrews' locomotor activity parameters (distance moved and rearing), whereas dexmedetomidine did not do so. The results suggest that dexmedetomidine represents a better candidate for antiemetic potential with advantages over clonidine.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Antieméticos , Clonidina , Dexmedetomidina , Musaranhos , Vômito , Ioimbina , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Clonidina/farmacologia , Clonidina/análogos & derivados , Clonidina/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Vômito/tratamento farmacológico , Vômito/induzido quimicamente , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Ioimbina/farmacologia , Modelos Animais de Doenças , Masculino , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Eméticos/farmacologia
2.
Drug Alcohol Depend ; 258: 111282, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38593731

RESUMO

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined.


Assuntos
Fentanila , Reforço Psicológico , Autoadministração , Xilazina , Fentanila/farmacologia , Animais , Xilazina/farmacologia , Ratos , Masculino , Feminino , Economia Comportamental , Ratos Sprague-Dawley , Esquema de Reforço , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos Opioides , Condicionamento Operante/efeitos dos fármacos
3.
Artigo em Inglês | MEDLINE | ID: mdl-38684422

RESUMO

PURPOSE: The study aims to assess the effects of dexmedetomidine (Dex) pretreatment on patients during cardiac valve replacement under cardiopulmonary bypass. METHODS: For patients in the Dex group (n = 52), 0.5 µg/kg Dex was given before anesthesia induction, followed by 0.5 µg/kg/h pumping injection before aortic occlusion. For patients in the control group (n = 52), 0.125 ml/kg normal saline was given instead of Dex. RESULTS: The patients in the Dex group had longer time to first dose of rescue propofol than the control group (P = 0.003). The Dex group required less total dosage of propofol than the control group (P = 0.0001). The levels of cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α) were lower in the Dex group than the control group at T4, 8 h after the operation (T5), and 24 h after the operation (T6) (P <0.01). The Dex group required less time for mechanical ventilation than the control group (P = 0.003). CONCLUSION: The study suggests that 0.50 µg/kg Dex pretreatment could reduce propofol use and the duration of mechanical ventilation, and confer myocardial protection without increased adverse events during cardiac valve replacement.


Assuntos
Biomarcadores , Ponte Cardiopulmonar , Dexmedetomidina , Implante de Prótese de Valva Cardíaca , Propofol , Respiração Artificial , Troponina I , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Humanos , Ponte Cardiopulmonar/efeitos adversos , Masculino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Feminino , Fatores de Tempo , Pessoa de Meia-Idade , Resultado do Tratamento , Propofol/efeitos adversos , Propofol/administração & dosagem , Biomarcadores/sangue , Troponina I/sangue , Creatina Quinase Forma MB/sangue , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Fator de Necrose Tumoral alfa/sangue , Malondialdeído/sangue , Idoso , Adulto , Anestésicos Intravenosos/efeitos adversos , Anestésicos Intravenosos/administração & dosagem , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/etiologia
4.
BMJ Open ; 14(4): e081637, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580355

RESUMO

INTRODUCTION: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes. METHODS AND ANALYSIS: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored. ETHICS AND DISSEMINATION: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement. TRIAL REGISTRATION NUMBER: NCT03653832.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Estado Terminal , Humanos , Estado Terminal/terapia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva , Cuidados Críticos/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Biomed Pharmacother ; 174: 116462, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38513598

RESUMO

BACKGROUND: Acute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α2-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models. METHODS: C57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 µg/kg), or LPS, Dex and Atipamezole (Atip, an α2-adrenoreceptor antagonist) (500 µg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 µg/ml) alone, LPS and Dex (1 µM), transforming growth factor-beta 1 (TGF-ß1) (5 ng/ml) alone, TGF-ß1 and Dex, with or without Atip (100 µM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined. RESULTS: Dex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-ß1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation. CONCLUSIONS: Dex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α2-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Dexmedetomidina , Fibrose , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos alfa 2 , Animais , Humanos , Camundongos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Linhagem Celular , Dexmedetomidina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Lipopolissacarídeos/farmacologia , Necroptose/efeitos dos fármacos , Fenótipo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo
6.
Paediatr Anaesth ; 34(5): 405-414, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38363011

RESUMO

BACKGROUND: Dexmedetomidine is a selective α2-adrenergic agonist originally approved for sedation of adults in the intensive care unit and subsequently approved for procedural sedation in adults undergoing medical procedures. Dexmedetomidine is widely used off-label for procedural sedation in children. AIMS: To evaluate efficacy and safety of monotherapy dexmedetomidine for magnetic resonance imaging procedural sedation of children ≥1month-<17years across three ascending doses. METHODS: Randomized, double-blind, dose-ranging study of procedural sedation recruited patients at USA and Japanese sites from February 2020 to November 2021. Patients were stratified into Cohort A (≥1month-<2years) or Cohort B (≥2-<17years). Cohort A loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.0 mcg/kg/1.0 mcg/kg/h, and 1.5 mcg/kg/1.5 mcg/kg/h. Cohort B loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.2 mcg/kg/1.0 mcg/kg/h, and 2.0 mcg/kg/1.5 mcg/kg/h. Primary endpoint was percentage of overall patients completing MRI without rescue propofol at the high versus low dose. Key secondary endpoint was percentage in each age cohort who did not require propofol at the high versus low dose. RESULTS: One hundred twenty-two patients received high- (n = 38), middle- (n = 42), or low-dose (n = 42) dexmedetomidine. A greater percentage completed MRI without propofol rescue, while receiving high- versus low-dose dexmedetomidine (24/38 [63.2%] vs. 6/42 [14.3%]) (odds ratio: 10.29, 95% confidence interval: 3.47-30.50, p < .001). Similar results were seen in both age cohorts. The most common adverse events were bradypnea, bradycardia, hypertension, and hypotension, and the majority were of mild-to-moderate severity. CONCLUSIONS: Dexmedetomidine was well tolerated. The high dose was associated with meaningfully greater efficacy compared with lower doses. Based on these results, the recommended starting dose for procedural sedation in children ≥1month-<2years is loading dose 1.5 mcg/kg/maintenance infusion 1.5 mcg/kg/h; children ≥2-<17years is loading dose 2.0 mcg/kg/maintenance infusion 1.5 mcg/kg/h.


Assuntos
Dexmedetomidina , Propofol , Adolescente , Criança , Humanos , Agonistas de Receptores Adrenérgicos alfa 2 , Sedação Consciente/métodos , Hipnóticos e Sedativos , Imageamento por Ressonância Magnética , Recém-Nascido , Lactente , Pré-Escolar
7.
Neuropsychopharmacology ; 49(6): 1014-1023, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38368493

RESUMO

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory α1-adrenergic receptors (α1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an α1-AR-mediated excitatory postsynaptic current (α1-AR-EPSC). Activation of inhibitory α2-adrenergic receptors (α2-AR) with UK-14,304 eliminated the α1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic α2-AR produced an outward current through activation of GIRK potassium conductance. Further, in vivo activation of α2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, α2-AR are critical regulators of serotonin neuron excitability.


Assuntos
Núcleo Dorsal da Rafe , Locus Cerúleo , Receptores Adrenérgicos alfa 2 , Neurônios Serotoninérgicos , Transmissão Sináptica , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/fisiologia , Núcleo Dorsal da Rafe/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Feminino , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Camundongos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Optogenética , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Camundongos Transgênicos
8.
Vet J ; 304: 106080, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38360134

RESUMO

Alpha-2-adrenoceptor agonist detomidine is a commonly used sedative agent in horses. In addition to the sedative effect, detomidine has been reported to elicit changes in energy metabolism such as hypoinsulinaemia and hyperglycaemia. This study aimed to investigate the effects of detomidine with and without peripherally acting alpha-2-adrenoceptor antagonist vatinoxan on insulin and blood glucose (BG) concentrations in horses after a standard dose of oral carbohydrates. Sixteen horses were assigned to four intravenous treatments in a randomised cross-over design: saline (SAL), detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), and a combination of detomidine and vatinoxan (DET+VAT). Horses were administered corn syrup (0.45 mL/kg) immediately before each treatment. Blood samples were collected until 360 min. The differences between treatments were evaluated with repeated measures analysis of covariance and change from baseline was used as a response. P<0.05 was considered significant. After oral carbohydrate load, DET reduced insulin (median 30 min nadir 3.7, min-max 0.6-7.4 µIU/mL) significantly compared with SAL (P<0.0001; 17.4, 9.3-65.4 µIU/mL) and DET+VAT (P=0.0005; 6.4, 2.9-12.9 µIU/mL). BG increased significantly after DET (peak; 130.5, 8.8-15.8 mmol/L) compared with SAL (P<0.0001; 8.7, 6.9-12.4 mmol/L) and DET+VAT (P<0.0001; 8.5, 6.8-10.6 mmol/L). Vatinoxan alone reduced BG (peak median 7.6, 7.0-9.9 mmol/L) compared with SAL (P=0.02) and delayed insulin responses to carbohydrates. In conclusion, vatinoxan alleviated the detomidine-induced changes (DET+VAT compared to DET) in insulin and BG after oral carbohydrate load. Additionally, vatinoxan is potentially able to modulate BG concentration and insulin response after oral carbohydrate administration in horses, but more research is warranted.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Imidazóis , Cavalos , Animais , Hipnóticos e Sedativos , Insulina , Estudos Cross-Over , Receptores Adrenérgicos , Carboidratos , Glucose
9.
PLoS One ; 19(2): e0292190, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38359044

RESUMO

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.


Assuntos
Adenina/análogos & derivados , Esclerose Lateral Amiotrófica , Cinamatos , Guanabenzo , Guanabenzo/análogos & derivados , Indóis , Tioureia/análogos & derivados , Camundongos , Humanos , Animais , Guanabenzo/farmacologia , Guanabenzo/uso terapêutico , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Clonidina , Resposta a Proteínas não Dobradas , Agonistas de Receptores Adrenérgicos alfa 2
10.
J Med Toxicol ; 20(2): 218-221, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38231419

RESUMO

INTRODUCTION: Guanfacine, an alpha-2 adrenergic agonist, is used to treat attention deficit hyperactivity disorder (ADHD). Although cardiovascular effects including hypotension and bradycardia are common adverse effects of guanfacine, the effect of guanfacine on QT intervals remains unclear. The association between the serum concentration of guanfacine and its toxicity has also not been fully investigated. CASE REPORT: This is a case of a 21-year-old woman with ADHD who developed repeated presyncope 1 day before admission. She was taking 3 mg of extended-release guanfacine and 50 mg of sertraline. On admission, she had bradycardia and hypotension. An electrocardiogram (ECG) showed a QT interval of 0.68 s and a QTcF interval of 0.648 s. The QT intervals were manually measured and corrected by the Fridericia formula (QTcF = QT/RR1/3). Although she denied taking an overdose of guanfacine and other drugs, we suspected guanfacine toxicity. The serum guanfacine concentration was 13.0 ng/mL on admission and decreased to 3.2 ng/mL on day 1 and 0.4 ng/mL on day 2. Changes in QTcF intervals and her vital signs correlated with serum guanfacine concentrations. CONCLUSION: Supratherapeutic serum guanfacine concentrations may induce QT prolongation.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Hipotensão , Feminino , Humanos , Adulto Jovem , Agonistas de Receptores Adrenérgicos alfa 2/toxicidade , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Bradicardia/induzido quimicamente , Guanfacina/toxicidade , Hipotensão/induzido quimicamente
11.
BMJ Support Palliat Care ; 13(e3): e876-e880, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-37076261

RESUMO

OBJECTIVES: Alpha-2 agonists have analgesic and sedative properties that can prove interesting in palliative care. The main objective of this study was to describe the use of clonidine and dexmedetomidine in palliative care units (PCU). The secondary objective was to identify physicians' perspectives and attitudes toward alpha-2-agonists. METHODS: International multicentric qualitative survey of prescribing characteristics and attitudes towards alpha-2 agonist. All 159 PCUs in France, Belgium and French-speaking Switzerland were contacted, and 142 physicians answered the questionnaire (31% participation). RESULTS: 20% of the practitioners surveyed prescribe these molecules are mainly for analgesic and sedative indications. There was considerable heterogeneity in the modalities and dosages of administration. The use of clonidine is more frequent and common in Belgium, while dexmedetomidine is only used in France. There is a high level of satisfaction among practitioners who use these molecules, with the desire of the majority of respondents to obtain additional studies and information on alpha-2-agonists. CONCLUSION: Alpha-2 agonists are little known and little prescribed by French-speaking palliative care physicians but are of interest because of their potential in this field. Phase 3 studies could justify the use of these molecules in palliative situations and would contribute to harmonising professional practices.


Assuntos
Dexmedetomidina , Medicina Paliativa , Humanos , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Analgésicos , Clonidina/uso terapêutico , Dexmedetomidina/uso terapêutico , Hipnóticos e Sedativos
12.
J Perinatol ; 44(2): 164-172, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37845426

RESUMO

Opioids and benzodiazepines have historically been employed for pain relief; however, they are associated with detrimental long-term neurodevelopmental consequences. Dexmedetomidine, a highly selective alpha-2-adrenoreceptor agonist, has piqued interest as a viable alternative for neonates, owing to its potential analgesic and neuroprotective attributes. We conducted a systematic review to assess the efficacy and safety of dexmedetomidine utilization in neonates. We conducted a comprehensive search of Ovid, MEDLINE, EMBASE, PubMed, Cochrane, and CINAHL, spanning from January 2010 to September 2022. Our review encompassed six studies involving 252 neonates. Overall, dexmedetomidine may be effective in achieving sedation and analgesia. Furthermore, it may reduce the need for adjunctive sedation or analgesia, shorten the time to extubation, decrease the duration of mechanical ventilation, and accelerate the attainment of full enteral feeds. Notably, no significant adverse effects associated with dexmedetomidine were reported. Nevertheless, additional well-designed studies to establish both the efficacy and safety of dexmedetomidine in neonatal care are needed.


Assuntos
Analgesia , Dexmedetomidina , Recém-Nascido , Humanos , Dexmedetomidina/efeitos adversos , Dor , Agonistas de Receptores Adrenérgicos alfa 2 , Manejo da Dor
13.
CNS Neurosci Ther ; 30(3): e14446, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37721421

RESUMO

BACKGROUND: The mechanism of pain symptoms in Parkinson's disease (PD) is unclear. Norepinephrine (NE) regulates neuropathic pain through ascending and descending pathways. However, the loss of NE neurons in the brain of patients with PD is obvious, it is speculated that NE is involved in the occurrence of PD pain symptoms. AIMS: To investigate the effect of NE on the activation of brain cells through adrenergic α2 receptor, so as to regulate the nociception threshold in a 6-OHDA-induced animal model of PD. METHODS: PD rat model was established by 6-OHDA injection (6-OHDA group). DSP-4 (or anti-DBH-saporin) was used to reduce the NE level of the PD rat brain. The heat sensitivity threshold (HST) and pressure withdrawal threshold (PWT) were measured. Tyrosine hydroxylase and NE in rat brains were detected by Elisa. The percentage of GFAP-positive cells in the prefrontal cortex, cingulate gyrus and striatum of rats was detected by immunohistochemistry and immunofluorescence. GFAP protein was semiquantified by method of western blot. Then yohimbine and guanfacine were used to increase the NE level in PD rats, and the above experimental changes were observed after drug application. RESULTS: The contents of NE in the brain of 6-OHDA-induced PD rats were lower than that of control group. After DSP-4 (or anti-DBH-saporin) injection, PD rats showed the lowest NE level (compared with 6-OHDA group, p ≤ 0.05), and after yohimbine and guanfacine were applied to 6-OHDA group, the contents of NE increased in the prefrontal cortex of rats. The HST and PWT of 6-OHDA group were significantly lower than those of control group, and after DSP-4 (or anti-DBH-saporin) injection, the HST and PWT of rats were lower than those of 6-OHDA group, and after the administration of yohimbine and guanfacine, both HST and PWT were significantly increased. GFAP-positive cells increased in prefrontal cortex and anterior cingulate gyrus of 6-OHDA group rats, and more significantly increased after DSP-4 (or anti-DBH-saporin) injection, and significantly reduced after yohimbine and guanfacine were used. CONCLUSIONS: The change of norepinephrine content can affect the activation of prefrontal and cingulate gyrus glial cells and participate in the regulation of nociception threshold in PD rats. Adrenergic α2 receptor agonist and central presynaptic membrane α2 receptor blocker both affect cell activation and improve hyperalgesia.


Assuntos
Benzilaminas , Norepinefrina , Doença de Parkinson , Humanos , Ratos , Animais , Norepinefrina/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Oxidopamina/toxicidade , Saporinas , Guanfacina , Nociceptividade , Ioimbina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2 , Dor , Modelos Animais de Doenças
14.
Paediatr Anaesth ; 34(2): 112-120, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37927199

RESUMO

BACKGROUND: During scoliosis surgery, motor evoked potentials (MEP), and somatosensory evoked potentials (SSEP) have been reported to be affected by the use of higher doses of anesthetic agents. Dexmedetomidine, a sympatholytic agent, an alpha-2 receptor agonist, has been used as an adjunctive agent to lower anesthetic dose. However, there is conflicting evidence regarding the effects of dexmedetomidine on the intraoperative neurophysiological monitoring of MEP and SSEP during surgery, particularly among pediatric patients. OBJECTIVES: This systematic review aimed to determine whether, during spinal fusion surgery in pediatric patients with scoliosis, dexmedetomidine alters MEP amplitude or SSEP latency and amplitude and, if so, whether different doses of dexmedetomidine display different effects (PROSPERO registration number CRD42022300562). METHODS: We searched PubMed, Scopus, and Cochrane Library on January 1, 2022 and included randomized controlled trials, observational cohort and case-control studies and case series investigating dexmedetomidine in the population of interest and comparing against a standardized anesthesia regimen without dexmedetomidine or comparing multiple doses of dexmedetomidine. Animal and in vitro studies and conference abstracts were excluded. RESULTS: We found substantial heterogeneity in the risk of bias (per Cochrane-preferred tools) of the included articles (n = 5); results are summarized without meta-analysis. Articles with the lowest risk of bias indicated that dexmedetomidine was associated with MEP loss and that higher doses of dexmedetomidine increased risk. In contrast, articles reporting no association between dexmedetomidine and MEP loss suffered from higher risk of bias, including suspected or confirmed problems with confounding, outcome measurement, participant selection, results reporting, and lack of statistical transparency and power. CONCLUSION: Given the limitations of the studies available in the literature, it would be advisable to conduct rigorous randomized controlled trials with larger sample sizes to assess the effects of dexmedetomidine use of in scoliosis surgery in pediatric patients.


Assuntos
Dexmedetomidina , Monitorização Neurofisiológica Intraoperatória , Escoliose , Humanos , Criança , Monitorização Neurofisiológica Intraoperatória/métodos , Dexmedetomidina/farmacologia , Escoliose/cirurgia , Potenciais Somatossensoriais Evocados/fisiologia , Potencial Evocado Motor/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Estudos Retrospectivos
15.
Vet Anaesth Analg ; 51(2): 144-151, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38103967

RESUMO

OBJECTIVE: To assess the effects of an α2-adrenoceptor agonist (detomidine) constant rate infusion (CRI) with and without an α2-adrenoceptor antagonist (vatinoxan) CRI on blood insulin and glucose concentrations, heart rate, intestinal borborygmi, and sedation during and after infusion in horses. STUDY DESIGN: Randomized, blinded, crossover, experimental study. ANIMALS: A total of nine healthy, adult Finnhorse mares. METHODS: Horses were treated with an intravenous (IV) detomidine loading dose (0.01 mg kg-1), followed by CRI (0.015 mg kg-1 hour-1), and the same doses of detomidine combined with an IV vatinoxan loading dose (0.15 mg kg-1), followed by CRI (detomidine and vatinoxan; 0.05 mg kg-1 hour-1) with an 18 day washout period. Infusion time was 60 minutes and horses were monitored for 240 minutes after the infusion. Heart rate, borborygmi score and sedation were assessed, and blood glucose, insulin and triglyceride concentrations were measured. Data were analyzed using repeated measures ancova and Wilcoxon signed-rank tests. Values of p < 0.05 were considered statistically significant. RESULTS: Insulin concentration decreased during (median nadir 1.7, range 0.0-2.9 µIU mL-1 at 60 minutes, p < 0.0001) and increased after detomidine CRI (median 36.6, range 11.7-78.4 µIU mL-1 at 180 minutes, p = 0.0001) significantly compared with detomidine and vatinoxan CRI. A significant elevation of blood glucose (peak 11.5 ± 1.6 mmol L-1 at 60 minutes, p < 0.0001) was detected during detomidine CRI. Vatinoxan alleviated the insulin changes and abolished the significant increase in blood glucose. Vatinoxan alleviated the decrease in heart rate (p = 0.0001) during detomidine infusion. No significant differences were detected in sedation scores between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan attenuated the negative adverse effects of detomidine CRI and thus is potentially beneficial when used in combination with an α2-adrenoceptor agonist CRI in horses.


Assuntos
Hipnóticos e Sedativos , Imidazóis , Insulina , Quinolizinas , Cavalos , Animais , Feminino , Glicemia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Receptores Adrenérgicos , Estudos Cross-Over
16.
Pharmacol Biochem Behav ; 235: 173694, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38128767

RESUMO

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence. On the thermal gradient ring, mice in the heroin withdrawal group preferred warmer temperatures, and the results depended on the ring's temperature range. On the dynamic cold plate, heroin withdrawal increased the number of nociceptive responses, with a temperature ramp from 4 °C to -1 °C yielding the largest response. On the stable cold plate, heroin withdrawal increased the number of nociceptive responses, and a plate temperature of 2 °C yielded the most significant increase in responses. Among the three tests, the stable cold plate elicited the most robust change in behavior between heroin-dependent and nondependent mice and had the highest throughput. To pharmacologically characterize the stable cold plate test, we used µ-opioid and non-opioid receptor-targeting drugs that have been previously shown to reverse OWIH in mechanical and heat nociception assays. The full µ-opioid receptor agonist methadone and µ-opioid receptor partial agonist buprenorphine decreased OWIH, whereas the preferential µ-opioid receptor antagonist naltrexone increased OWIH. Two N-methyl-d-aspartate receptor antagonists (ketamine, MK-801), a corticotropin-releasing factor 1 receptor antagonist (R121919), a ß2-adrenergic receptor antagonist (butoxamine), an α2-adrenergic receptor agonist (lofexidine), and a 5-hydroxytryptamine-3 receptor antagonist (ondansetron) had no effect on OWIH. These data demonstrate that the stable cold plate at 2 °C yields a robust, reliable, and concise measure of OWIH that is sensitive to opioid agonists.


Assuntos
Hiperalgesia , Síndrome de Abstinência a Substâncias , Humanos , Camundongos , Animais , Hiperalgesia/induzido quimicamente , Heroína/efeitos adversos , Analgésicos Opioides/farmacologia , Nociceptividade , Entorpecentes/efeitos adversos , Dor/tratamento farmacológico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Agonistas de Receptores Adrenérgicos alfa 2 , Receptores Opioides
17.
BMJ Open ; 13(12): e078645, 2023 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-38072483

RESUMO

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.


Assuntos
Dexmedetomidina , Propofol , Adulto , Humanos , Propofol/uso terapêutico , Dexmedetomidina/uso terapêutico , Análise Custo-Benefício , Clonidina/uso terapêutico , Estado Terminal/terapia , Qualidade de Vida , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Dor/induzido quimicamente , Unidades de Terapia Intensiva , Reino Unido , Respiração Artificial , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como Assunto
18.
J Toxicol Sci ; 48(12): 641-644, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38044125

RESUMO

Guanfacine hydrochloride extended-release (GXR) is used to treat attention deficit hyperactivity disorder. It is a selective α2A-adrenorecepor agonist that was reported to cause QT prolongation and hypotension in the event of overdosing. We report the case of a 17-year-old man who took 226 tablets of GXR 3 mg for attempted suicide. He was found complaining of dyspnea, and emergency medical services were called. When the patient was transferred to our hospital, his Glasgow coma scale was 12 (E4V3M5). He was agitated and hypoxemic. He was intubated for invasive mechanical ventilation under sedation. His chest X-ray and computed tomography scan showed pulmonary edema. Transthoracic echocardiography showed markedly reduced cardiac function. His serum guanfacine concentration peaked on day 3 after admission. His pulmonary edema improved quickly after a decrease in serum guanfacine concentration, but cardiac decompensation persisted for about 1 month. This case reveals that the decline in cardiac function after guanfacine intoxication is prolonged even after its serum concentration has decreased.


Assuntos
Guanfacina , Edema Pulmonar , Adolescente , Humanos , Masculino , Agonistas de Receptores Adrenérgicos alfa 2/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Preparações de Ação Retardada/efeitos adversos , Guanfacina/sangue , Guanfacina/toxicidade , Edema Pulmonar/induzido quimicamente
19.
Prensa méd. argent ; 109(5): 193-214, 20230000. fig, tab
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1523561

RESUMO

La dependencia del alcohol se encuentra entre los principales factores de riesgo para la salud en la mayoría de los países desarrollados y en desarrollo.El éxito terapéutico en la abstinencia modera-grave podría incrementarse con tratamiento adyuvante a las benzodiacepinas. En nuestro medio los agonistas alfa2 (clonidina y dexmedetomidina), ácido valproico y carbamazepina son los de mayor uso. El objetivo de este trabajo fue realizar la búsqueda exhaustiva, análisis crítico y resumen de la evidencia para proporcionar una visión general de la efectividad de estos fármacos cuando son utilizado sin tiempo determinado de tratamiento comparados entre sí, contra ninguna intervención, placebo u otras intervenciones. Se realizó una búsqueda bibliográfica en bases de datos (Pubmed/MEDLINE, LILACs, EMBASE). Dos revisores seleccionaron, extrajeron los datos y evaluaron el riesgo de sesgo de los estudios incluidos de forma independiente mediante el software Covidence. Los desacuerdos fueron resueltos por consenso. Realizamos metanálisis utilizando RevMan 5. 3 y análisis de subgrupos por diseño de estudio. Se incluyeron 22 estudios donde ninguno de ellos presentó bajo riesgo de sesgo en todos los dominios, y la mayoría de los estudios presentaron al menos un dominio con alto riesgo de sesgo. Estudios con resultados estadísticamente bajos mostraron que la dexmedetomidina y el ácido valproico disminuyen los requerimientos de benzodiacepinas en pacientes que recibían placebo. Además, cuando se combinan ácido valproico con benzodiacepinas logran una disminución estable y continua de la abstinencia medido en escala CIWA-Ar. La clonidina fue la única descripta que presentaba disminución en la frecuencia cardiaca frente a placebo con alta significancia, situación clínica a tener presente frente al síndrome simpaticomimético que caracteriza al síndrome de abstinencia por alcohol.


Alcohol dependence is among the main risk factors for health in most developed and developing countries. Therapeutic success in moderate-Grave abstinence could be increased with adjuvant treatment to benzodiazepines. In our environment, agonists Alfa 2 (clonidine and dexmedetomidine), valproic acid and carbamazepine are the most used. The objective of this work was to carry out the thorough search, critical analysis and summary of the evidence to provide an overview of the effectiveness of these drugs when used without a certain time of treatment compared to each other, against any intervention, placebo or other interventions. A bibliographic search was carried out in databases (Pubmed/ Medline, Lilacs, Embase). Two reviewers selected, extracted the data and evaluated the bias risk of independently included studies using the COVIDENCE software. The disagreements were resolved by consensus. We perform meta-analysis using Revman 5. 3 and subgroup analysis by study design. 22 studies were included where none of them presented under a risk of bias in all domains, and most studies presented at least one domain with high bias risk. Studies with statistically low results showed that dexmedetomidine and valproic acid decrease the requirements of benzodiazepines in patients receiving placebo. In addition, when valproic acid is combined with benzodiazepines achieve a stable and continuous decrease in abstinence measured in CIWA-AR scale. Clonidine was the only one described that presented a decrease in heart rate against placebo with high significance, clinical situation to be in mind in front of the sympathomimetic syndrome that characterizes alcohol withdrawal syndrome


Assuntos
Humanos , Masculino , Feminino , Benzodiazepinas/uso terapêutico , Consumo de Bebidas Alcoólicas/terapia , Resultado do Tratamento , Agonistas de Receptores Adrenérgicos alfa 2 , Abstinência de Álcool
20.
Eur J Pharmacol ; 959: 176090, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37778612

RESUMO

BACKGROUND: Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models. METHODS: Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models. RESULTS: There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)). CONCLUSIONS: DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.


Assuntos
Dexmedetomidina , Traumatismo por Reperfusão , Ratos , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Ratos Sprague-Dawley , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Traumatismo por Reperfusão/patologia , Inflamação/tratamento farmacológico , Isquemia/tratamento farmacológico
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